Certain pyrimidinylbenzenesulfonamides



3,520,887 CERTAIN PYRIMIDINYLBENZENESULFON- AMIDES Ruth Heerdt,Mannheim-Feudenheim, Manfred Hubner,

Ludwigshafen (Rhine), Felix Helmut Schmidt, Mannheim-Neuostheim, KurtStach, Mannheim-Waldhof, and Helmut Weber, Frankfurt am Main,Schwanheim, Germany, assignors to Boehringer Mannheim, GmbH, Antsgeicht,Mannheim, Germany No Drawing. Filed Nov. 15, 1967, Ser. No. 683,130Claims priority, application Germany, Nov. 29, 1966, B 90,051 Int. Cl.C0711 51/46 US. Cl. 260-2565 15 Claims ABSTRACT OF THE DISCLOSURE Anovel class of sulfonamides is disclosed, the same constitutingantidiabetic agents having marked blood sugar reducing activity. Thecompounds have the following formula:

wherein A is unsubstituted or substituted alkyl, alkenyl, aryl, aralkyl,aryloxyalkyl, arylmercaptoalkyl, cycloalkyl, cycloalkenyl, thienyl,furyl, alkoxy, alkenyloxy, aralkoxy, cycloalkoxy or a group having theformula:

wherein V and W are each hydrogen, unsubstituted or substituted alkyl,cycloalkyl, aryl or aralkyl and taken together with the nitrogen atom towhich they are attached form an unsubstituted or substituted saturatedheterocyclic ring, R is hydrogen, lower alkyl or aralkyl, X is astraight or branched chain hydrocarbon radical containingup to 4 carbonatoms, R is lower alkyl and R is hydrogen, unsubstituted or substitutedalkyl, cycloalkyl, aryl, aralkyl, alkoxy, alkoxyalkyl and alkoxyalkoxy,wherein R and R taken together form a ring of 3 to 5 methylene groupswhich can contain oxygen or sulfur atoms.

Novel compositions containing the aforesaid sulfonamides as activeingredient as well as a method of using such compositions are alsodisclosed.

This invention relates to novel therapeutic sulfonamides, tocompositions containing the same as active ingredients and to a methodof using the same.

More particularly this invention relates to compositions of matterclassified in the art of chemistry as benzenesulfonylamido pyrimidineswhich are characterized by a marked and particularly prolongedantidiabetic activity.

In accordance with the invention it has now been found thatbenzenesulfonamido pyrimidines which contain a carbamido alkylsubstituent in the beruene nucleus are characterized by marked andprolonged antidiabetic activity. The sulfonamides in accordance with theinvention are represented by the following formula:

wherein A is unsubstituted or substituted alkyl, alkenyl, aryl, aralkyl,aryloxyalkyl, arylmercaptoalkyl, cycloalkyl,

inited States Patent 0 cycloalkenyl, thienyl, furyl, alkoxy, alkenyloxy,aralkoxy, cycloalkoxy, cycloalkylalkoxy, cycloalkenyloxy,cycloalkenylalkoxy or a group having the formula:

wherein V and W, which may be the same or different, are each hydrogenor unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl andwhen taken together with the nitrogen atom to which they are attachedform an unsubstituted or substituted saturated heterocyclic ring, R ishydrogen, lower alkyl or aralkyl, X is a straight or branched-chainhydrocarbon radical containing up to 4 carbon atoms, R is lower alkyland R is hydrogen or unsubstituted or substituted alkyl, cycloalkyl,aryl, aralkyl, alkoxy, alkoxyalkyl or alkoxyalkoxy, wherein R and Rtaken together can also form a ring of 3 to 5 methylene groups whichring can be interrupted by oxygen or sulfur atoms. The invention alsoincludes the pharmaceutically acceptable alkali salts of the compoundsI.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same as follows.

The novel sulfonamides of the present invention can be preparedaccording to the known methods, as for example, by the followingmethods:

(a) A compound of the formula:

in @smnm wherein A, R and X have the same meanings as given above and nis 0, l or 2, is reacted with a Z-amino-pyrimidine of the formula:

wherein R and R have the same meanings as given above, wherea'fter, ifnecessary, the product obtained is oxidized to provide the desiredsulfonamide; or

(b) A benzene-sulfonyl-guanidine of the formula:

wherein A, R and X have the same meanings as given above, is reactedwith a compound of the formula:

Z-OO(|1H-COR2 a wherein R and R have the same meanings as given aboveand Z is hydrogen or alkoxy, or with a functional deriv-' given above,is reacted with a reactive derivative of an acid of the formula A.COOH,wherein A has the same meaning as given above; or

wherein X, R R and R have the same meanings as 3 (d) A sulfonamide ofthe formula:

A-oo-N-x wherein A, R and X have the same meanings as given above, isreacted with a pyrimidine derivative of the forwherein R and R have thesame meanings as given above and T is a reactive ester group or a lowermolecular trialkylammonium group. Thereafter, if desired, the productwhich is obtained is converted, in the conventional manner, into itscorresponding physiologically compatible salt.

The reaction of compounds (II) and (III) is advantageously carried outin an inert solvent in the presence of a base, preferably pyridine ortrimethylamine. However, it is also possible to use twice the amount ofthe aminopyiri'midine (III) in order to remove the hydrogen chlorideformed by the reaction. The oxidation of the sulfenamides orsulfinamides which follows is carried out in the conventional manner asfor example, by the action of hydrogen peroxide, potassium permanganateor nitric acid.

The benzene-sulfonyl-guanidines (IV) used as starting materials can beprepared, for example, by melting together the correspondingbenzene-sulfonamides with guanidine carbonate. The condensation with thefl-dicarbonyl compounds (V) can be carried out, for example, by means ofan alkali metal alcoholate in an alcohol. The [El-dicarbonyl compounds(V) can in this connection be used either in the free form or in theform of a functional derivative thereof, such as for example theircorresponding acetals. They can, however, also be prepared in a one potprocess using the Vilsmeier method starting from the ketals of thecorresponding enamines, inorganic acid chlorides and dialkyl-formamides.If, in place of the dicarbonyl compounds, there are used thecorrespondingly substituted B-keto esters or their functionalderivatives, then the hydroxyl group present in the 6-position of thepyrimidine ring must thereafter be replaced by a hydrogen atom. This canbe carried out for example, by replacing the hydroxyl group with achlorine atom by means of an inorganic acid chloride, which canthereafter be easily removed through reduction with, for example, zincdust.

The acylation of the compounds (VI) is carried out in the conventionalmanner, as for example, by reaction with the corresponding acid halides,preferably in the presence of an acid acceptor, or with reactivederivatives thereof. When A represents a substituted hydroxyl group, itis advantageous to employ as starting materials chlorocarbonic acidesters or the corresponding orthocarbonic acid esters. The radical:

(VII) (VIII) can be introduced by reaction with carbamic acid halides orthe corresponding isocyanates. However, the compounds (VI) can alsofirst be reacted with phosgene and the intermediate products thusobtained thereafter reacted with an appropriate alcohol or with an amineof the formula:

As starting materials having structural Formula VIII, it is especiallypreferred to use the 2-halopyrimidines.

These can be obtained, for example, by the reaction of2-hydroxy-pyrimidines with excess phosphorus oxychloride. Thecondensation reaction, according to the present invention, with thebenzene-sulfonamides (VII) preferably takes place in the presence of abase, such as potassium carbonate. In place of the 2-halopyrimidines,there can also be used the corresponding trialkylammoniurn pyrimidines,with which the sulfonamides react to give the desiredbenzene-sulfonamido-pyrimidines, a trialkylamine also being formed as aby-product.

The pharmaceutically acceptable alkali salts of the sulfonamidesembraced by the above Formula I are also included within the scope ofthis invention since such salts are effective for use in our noveltherapeutic process be cause of their content of active sulfonamide.

The preferred pharmaceutically effective salts of the new sulfonamidesof the present invention are those with ammonia, the alkali metals andthe alkaline earth metals. They can be obtained, for example, byreaction of the free sulfonamide with sodium hydroxide solution,potassium hydroxide solution or an aqueous solution of ammonia or byreaction of the free sulfonamide with the corresponding carbonates.

This invention is further illustrated by the following examples whichdisclose the preparation of compounds illustrative of this invention.

EXAMPLE 1 4- ,8-5 '-chloro-2'-methoxy-benzamino-ethyl -N- [4-methyl-5-isobutyl-pyrimidinyl- 2) ]-benzene-sulfonamide 3.4 g.4-(18-5'-chloro-2-methoxy-benzamino ethyl)- benzene-sulfochloride (M.P.106-109" C.) were added to 1.7 g. 2-amino-4-methyl-5-isobutyl-pyrimidine(M.P. 158 C.) in 6 ml. anhydrous pyridine. The reaction mixture wasfirst allowed to stand for 1.5 hours at ambient temperature, then heatedfor 2 hours on a steam bath and, after cooling, poured into Water. Theproduct which thereupon precipitated out was filtered off and dissolvedin a dilute solution of sodium hydroxide. The solution was treated withactivated charcoal and filtered and the sulfonamide product precipitatedout of the filtrate with dilute hydrochloric acid. After filtering offthe precipitate with suction, the recovered product was purified byrecrystallizing it twice from ethanol. There were recovered 1.7 g. (33%of theory)4-(,B-5'-chloro-2'-methoxy-benzamino-ethyl)-N-[4-methyl-5-isobutyl-pyrimidinyl(2)]- benzene-sulfonamide having a melting point of 174 175 C.

The following compounds were prepared in an analogous manner:

4 (B 5 chloro 2' methoxy benzamino ethyl)- N [4 butyl pyrimidinyl (2)]benzene-sulfonamide; M.P. 139-140 C. (recrystallized from ethylacetate), as starting material there was used2-amino-4-butyl-pyrimidine; M.P. -107 C.;4-(fl-5'-chloro-2'-methoxy-benzamino ethyl) N [4 isobutyl pyrimidinyl(2)]- benzene-sulfonamide; M.P. 166 C. (recrystallized from ethanol), asstarting material, there was used 2-amino-4- isobutyl-pyrimidine; M.P.119-120" C.;

4 (,3 5' chloro 2' methoxy benzamino ethyl)- N-[4 methyl 5 propylpyrimidinyl (2)] benzenesulfonamide; M.P. 188-189 C.; for purification,the latter compound was successively recrystallized from methyl ethylketone, methanol and ethylene chloride, as starting material, there wasused 2-amino-4-methyl-5-propylpyrimidine; M.P. 163 C.;

4 (,3 5' chloro 2' methoxy benzamino ethyl)- N [4 methyl 5 isopropylpyrimidinyl (2)]- benzene-sulfonamide; M.P. 178-180 C.; the compound waspurified by recrystallizing the sodium salt from water and then the freecompound from ethanol, as starting material there was used2-amino-4-methyl-S-isopropylpyrimidine; M.P. -146" C.;

4 (B 5' chloro 2' methoxy benzamino ethyl)- N [5,6,7,8tetrahydroquinazolinyl (2)] benzenesulfonamide; M.P. 204-207 C.(recrystallized from chloroform/methanol), as startingmaterial there wasused 2 amino 5,6,7,8 tetrahydroquinazoline; MP 208- 210 C.; I

4 (,8 benzamino ethyl) N [5,6,7,8 tetrahydroquinazolinyl (2)] benzenesulfonamide; M.P. 218- 220 C. (recrystallized from ethylene glycol);

4 (B 5 chloro 2' ethoxy benzamino ethyl)- N [4 methyl 5 isopropylpyrimidinyl (2)] benzene-sulfonamide; M.P. 173 C. (recrystallized frommethanol), as starting material there was used 4-(fi-5-chloro- 2' ethoxybenzamino ethyl) benzene sulfochloride; M.P. 123125 C.; and

4 (5 5' chloro 2' ethoxy benzamino ethyl)- N [4 methyl 5 isobutylpyrimidinyl (2) 1-benzenesulfonamide; M.P. 183 C. (recrystallized fromethanol).

EXAMPLE 2 4- B-ethoxycarbonylamino-ethyl -N-5,6,7,8-tetrahydroquinazolinyl- 2) -benzene-sulfonamide 11 g. 2 amino5,6,7,8 tetrahydroquinazoline were introduced, with cooling, into 21.5g. 4-(fi-ethoxycarbonylamino ethyl) benzene sulfochloride (M.P. 68-71C.) in 30 ml. anhydrous pyridine. The reaction mixture was allowed tostand overnight at room temperature and then heated on a steam bath forone hour. After cooling, the reaction mixture was poured into water. Thecrystals which thereby precipitated out were filtered off with suctionand dissolved in dilute sodium hydroxide solution. The solution of thesodium salt thus obtained was treated with activated charcoal and thefree compound then precipitated out by the addition of hydrochloricacid. Following recrystallization from ethanol, there were obtained 16g. (53.5% of theory) 4-(B-ethoxy-carbonylaminoethyl) N [5,6,7,8tetrahydroquinazolinyl (2)]- benzene-sulfonamide, having a melting ponitof 168- 169 C.

In an analogous manner there were obtained 4-( 3- ethoxycarbonylaminoethyl) N [4 methyl 5 isobutyl pyrimidinyl (2)] benzene sulfonamide; M.P.166 C. (recrystallized from ethanol).

EXAMPLE 3 4- (fi-acetaminoethyl -N- 5,6,7,S-tetrahydroquihazolinyl- (2)]-benzene-sulfonamide A solution of 11 g. phosgene in 11 ml. methylenechloride was added, with stirring and ice cooling, to a solution of 7.3g. dimethyl formamide in 15 ml. methylene chloride. The resultantcrystalline slurry was allowed to stand at ambient temperature for 3hours. At about 5 C. a solution of 15.1 g. 1-pyrrolidino-cyclohexene in11 ml. methylene chloride was added thereto. Following the distillingoff of a part of the solvent, 50 ml. methanol were added and theremainder of the methylene chloride distilled off. The mixture which wasthereby obtained, was neutralized with a solution of sodium methylate,mixed with 22.7 g. 4-(fl-acetaminoethyl)-benzene-sulfonyl-guanidine(M.P. 120 C.) and with a further 36 g. of 30% sodium methylate solutionand then heated under reflux for 10 hours. After cooling, the mixturewas filtered with suction, the residue taken up in water, the resultantsolution filtered through charcoal and hydrochloric acid added to thefiltrate to precipitate out 4-(fl-acetaminoethyl)-N-[5,6,7,S-tetrahydroquinazolinyl (2)] benzene sulfonamide. The initiallyoily product which precipitated out was triturated with ethanol and wasthereby caused to crystallize. Further amounts of the product could berecovered from the evaporated methanolic filtrate. Afterrecrystallization from ethanol, the yield of4-(fl-acetaminoethyl)-N-[5,6,7,8-tetrahydroquinazolinyl (2)]benzenesulfonamide amounted to 6 g. of theory) and had a melting pointof 184 C. The analytical results corresponded to a monohydrate.

6 EXAMPLE 4 4 (B 4 chloro 2' methoxy benzamino ethyl) N- [4 methyl 5isobutyl pyrimidinyl (2)] benzenesulfonamide 3.48 g.4-(B-aminoethyl)-N-[4-methyl-5-isobutyl-pyrimidinyl-(2)1-benzene-sulfonamidewere dissolved in 5 ml. 2 N sodium hydroxide solution, diluted with somewater and a solution of 2.1 g. 4-chloro-2-methoxy-benzoylchloride in 5ml. methylene chloride slowly added thereto in dropwise fashion. Thereaction mixture was then stirred for one hour at ambient temperatureand the material precipitated out thereby filtered off with suction,washed with a little methylene chloride, dissolved in a dilute solutionof sodium hydroxide and again precipitated by the addition of dilutehydrochloric acid. There were thusly obtained 3.9 g. of theory)4-(pl-4'-chloro-2-methoxy-benzamino ethyl) N [4 methyl 5isobutyl-pyrimidinyl- (2) ]-benzene-sulfonamide having a melting pointof 183 C.

The 4-(,8-aminoethyl)-N-[4-methyl-5-isobutyl pyrimidinyl (2)] benzenesulfonamide (M.P. 197-199" C.) which was used as starting material wasprepared by the alkaline hydrolysis of the urethane prepared accordingto the procedure described in Example 2.

The following compounds were obtained in an analogous manner:

4 (5 5' bromo 2 methoxy benzamino ethyl)- N [4 methyl 5isobutyl-pyrimidinyl (2)] benzenesulfonamide; M.P. 179-l80 C.; and

4 (fl 3 methoxy thenoyl (2) amino ethyl)- N [4 methyl 5isobutyl-pyrimidinyl (2)] benzenesulfonamide; M.P. 157 C.(recrystallized from ethanol).

EXAMPLE 5 In a manner analogous to that described in Example 4, therewere obtained from 4-(B-aminoethyD-N-[5,6,7,8-tetrahydroquinazolinyl-(2)]-benzene-sulfonamide the following compounds:

4 (,8 3 chlorobenzamino ethyl)-N-[5,6,7,8-tetrahydroquinazolinyl- 2)-benzene-sulfonamide; M.P. 180- 18l C. (recrystallized from ethanol);

4 (,3 2 methoxy 5' methyl benzamino ethyl)- N [5,6,7,8tetrahydroquinazolinyl (2)] benzene-sulfonamide; M.P. 194-l95 C.(recrystallized from etha- 1101); and

4 (B phenylmercapto-acetamino-ethyl) N [5,6,7,8-

tetrahydroquinazolinyl (2)] benzene sulfonamide; for

purification, after reprecipitation, the latter product was successivelyrecrystallized from ethylene chloride and dioxan; M.P. 191-193 C.

The 4- (fi-aminoethyl -N- [5,6,7,S-tetrahydroquinazolinyl-(2)]-benzene-sulfonamide (M.P. 2l0-2l2 C.)used as starting material was obtained by the alkaline hydrolysis of theurethane which had been prepared according to Example 2 or of the acetylcompound prepared according to Example 3.

EXAMPLE 6 4- (fi-cyclohexane-carbonaminoethyl) -N- 5,6,7,8-tetrahydroquinazolinyl- (2) ]-benzene-sulfonamide 1.3 g.cyclohexane-carboxylic acid chloride were added to 3 g.4-(B-aminoethyl)-N-[5,6,7,8-tetrahydroquinazolinyl-(2)]-benzene-sulfonamidein 5 ml. anhydrous pyridine. The reaction mixture was allowed to standfor 4 hours at ambient temperature then heated for 1 hour on a steambath, and, after cooling, poured into water. The resultant precipitatedmaterial was dissolved in dilute sodium hydroxide solution, the solutionfiltered over activated charcoal and dilute hydrochloric acid added tothe filtrate to precipitate out 4-(fi-cyclohexane-carbonaminoethyl)-N-[5,6,7,8 tetrahydroquinazolinyl (2)] benzene-sulfonamide. Followingrecrystallization from ethanol, the yield of sulfonamide was 1.4 g. (32%of theory) and the compound had a melting point of 240 C.

7 In an analogous manner there was prepared 4-(,8-2'- methoxy benzaminoethyl) N [5,6,7,8 tetrahydroquinazolinyl-(Z) ]-benzene-sulfonamide; M.P.201202 C. (recrystallized from ethanol/ethylene chloride).

EXAMPLE 7 4-(fi-3-methyl-3-phenylureido-ethyl)-N-[4-rnethyl-5-isobutyl-pyrimidinyl-(2) ]-benzene-sulfonamide A solution of 3.48 g. 4(B-aminoethyD-N-[4-methyl-S-isobutyl-pyrimidinyl-(2)]benzene-sulfonamide in ml. 2 N sodiumhydroxide solution was diluted with a little water and a solution of 1.7g. methyl-phenyl-carbamoyl chloride in 5 ml. of methylene chlorideslowly added thereto in dropwise fashion. The resultant reaction mixturewas thereafter stirred for one hour at ambient temperature. Theprecipitated material which formed was filtered oil? with suction,washed with methylene chloride, dissolved in a dilute solution of sodiumhydroxide and the product again precipitated out by the addition ofdilute hydrochloric acid. There were recovered 3.7 g. (77% of theory) 4(,8 3 methyl-3-phenylureido-ethyl)-N- [4 methylS-isobutyl-pyrimidinyl-(2)J-benzene-sulfonamide having a melting pointof l54156 C.

In an analogous manner there was obtained 4-(13-indoline 1carbonamino-ethyl) N[5,6,7,8-tetrahydroquinazolinyl-(2)]-benzene-sulfonamide; forpurification, the product was first recrystallized from ethanol/ethylenechloride, then dissolved in a dilute solution of sodium hydroxide andprecipitated out by introduction of carbon dioxide; M.P. 236238 C.

EXAMPLE 8 4- fi-benzaminoethyl -N- 6,7 ,8,9-tetrahydro-5H-cycloheptad]-pyrimidin-2-yl -benzene-sulfonamide 4.15 g. 4-(pbenzaminoethyl)-benzene-sulfony1-guanidine (M.P. 278-279 C.) and 2.0 g.Z-fOrmyl-cycloheptanone were boiled under reflux for 8 hours in 20 ml.of glacial acetic acid. The glacial acetic acid was evaporated off in avacuum the residue stirred with water, filtered with suction, dissolvedin dilute sodium hydroxide solution and filtered oil from the unreactedsulfonyl-guanidine. After treatment with activated charcoal andfiltering, carbon dioxide was introduced into the filtrate until thesaturation point had been reached, the precipitate thereby formedfiltered oil with suction, boiled out with ethanol and againreprecipitated using the same procedure as before. There was obtained2.2 g. 4-(,8-benzaminoethyl)-N-(6,7,8,9-tetrahydro SH-cyclohepta [d]-pyrimidin-Z-yl)-benzene-sulfonamide (40.6% of theory), having a meltingpoint of 206207 C.

EXAMPLE 9 4- ()3-4'-flu0robenzamino-ethyl-N-[4-methyl-5-propylpyrimidinyl-(2)]-benzene-sulfonamide In a manneranalogous to that described in Example 1, there was obtained from 4(,B-4'-fluorobenzamino-ethyl)-benzene-sulfochloride (M.P. 131-134 C.)and 2- amino-4-methyl-5-propyl-pyrimidine, in 42% yield, 4-(19-4-fluorobenzamino-ethyl) N [4amethyl 5propyl-pyrimidinyl-(2)]-benzene-sulfonamide which followingrecrystallization from ethanol, had a melting point of 187- 188 C.

' EXAMPLE 10 4 (N-methyl-fi-5-chloro-2'-methoxy-benzamino-ethyl)-N-(6,7,8,9-tetrahydro 5H cyclohepta-[d]-pyrimidin- 2-yl)-benzene-sulfonamide 5.4 g. of 4-(N-methyl ,9 5'chloro-2'-methoxybenzamino-ethyl)-benzene-sulfochloride were added to2.2 g. Z-amino-6,7,8,9-tetrahydro 5H cyclohepta-[d]-pyrimidine (M.P. 146C.) in 10 ml. anhydrous pyridine, the reaction mixture allowed to standovernight, then heated for 1 hour on a steam bath and, after cooling,poured into 50 ml. water. The substance which was thereby precipitatedout was filtered otr', dissolved in dilute sodium hydroxide solution,the solution treated with activated charcoal and the product thenprecipitated out by acidification with dilute hydrochloric acid. Theprecipitate which formed by filtered off with suction and thenrecrystallized from a mixture of ethanol and chloroform. There wasthusly obtained 3.8 g. (54% of theory) 4-(N- methyl B 5'chloro-2'-methoxy-benzamino-ethyl)-N- (6,7,8,9 tetrahydro 5Hcyclohepta-[d]-pyrimidin-2- yl)-benzene-sulfonamide with a melting pointof 195- 196 C.

In an analogous manner there was obtained 4 (ti-5'- chloro 2'methoxy-benzamino-ethyl)-N-(6,7,8,9 tetrahydro-5H cyclohepta [d]pyrimidin-2-yl)-benzenesulfonamide; for purification, the sodium salt ofthis compound was recrystallized from water and the free compoundprecipitated out by introduction of carbon dioxide up to the saturationpoint; M.P. 187189 C.

EXAMPLE 1 1 4- (fi-phenoxyaceto amino-ethyl) -N- [4-methyl-5-isobutyl-pyrimidinyl- (2) -benzene-sulfonamide 1.7 g. 4-(aminoethyl) N[4-methyl 5 isobutyl-pyrimidinyl(2)]-benzene-sulfonamide were dissolvedin 2.5 ml. 2 N sodium hydroxide solution, diluted with some water and,while stirring and cooling, a solution of 0.85 g. phenoxyacetyl chloridein 3 ml. methylene chloride slowly added thereto in dropwise fashion.The reaction mixture was stirred for 2 hours at ambient temperature, theprecipitated material then filtered off with suction, washed with waterand ether, dissolved in dilute sodium hydroxide solution and againprecipitated out by the addition of dilute hydrochloric acid. Theproduct was thereafter recrystallized from methanol. There was obtained2.0 g. of theory) 4 (5 phenoxyacetamino-ethyl)- N [4-methyl 5isobutyl-pyrimidinyl-(2)]-benzenesulfonamide having a melting point ofC.

In an analogous manner, there were obtained the following compounds:

4-(fl-hydrocinnamoylamino-ethyl)-N- [4 methyl-5 isobutyl-pyrimidinyl-(2) J-benzene-sulfonamide; M .P. 167 C. (recrystallized from methanol);

4 (fi-2',5' dimethoxy-benzamino-ethyl)-N- [4-methyl-S-isobutyl-pyrimidinyl-(2)] benzene sulfonamide; M.P. 169 C. (afterdissolving in dilute sodium hydroxide solution and precipitating outwith dilute hydrochloric acid);

4-(fi-o-toluoylamino-ethyl)-N-[4-methyl 5 isobutylpyrimidinyl- (2)]-benzene-sulfonamide; M.P. 170 C. (recrystallized from methanol); and

4-(,B-m-toluoylamino-ethyl)-N-[4-methyl 5isobutylpyrimidinyl-(Z)]-benzene-sulfonamide; M.P. ISO-182 C.(recrystallized from methanol).

EXAMPLE 12 4- (fl-5'-chloro-2'-methoxy-benzamino-ethyl) -N- [4,5-diethyl-pyrimidinyl- (2) ]-benzene-sulfonamide 3.9 g. 4 ()3 5'chloro-2'-methoxy-benzamino-ethyl)- benzene-sulfochloride were added,with stirring and cooling, to 1.5 g. 2-amino-4,S-diethyl-pyrimidine(M.P. 131 C.) in 6 ml. anhydrous pyridine. The reaction mixture wasfirst allowed to stand for 2 hours at ambient temperature and thenheated for 2 hours on a steam bath. Following cooling, the mixture waspoured into 50 ml. water. The substance which was thereby precipitatedout was filtered off, dissolved in dilute sodium hydroxide solution, thesolution treated with activated charcoal, filtered and the free compoundprecipitated out from the filtrate by acidification with dilutehydrochloric acid. The precipitated product was thereafterrecrystallized from a methanol. There was recovered 2.6 g.4-(,B-S'-chloro-2'- methoxy-benzamino-ethyl) N [4,5-diethyl-pyrimidinyl-(2)]-benzene-sulfonamide (52% of theory) having a melting point of176177 C.

The following compounds were obtained in an analogous manner:

4(1&5'-chloro-2'-methoxy-benzamino-propyl) N -[4-methyl-S-isobutyl-pyrimidiny1 (2)] benzene-sulfonamide; forpurification, the compound was first recrystallized from methanol, thendissolved in dilute sodium hydroxide solution and fractionallyprecipitated with dilute acetic acid; M.P. 172-175 C.; and

4-(6-5'-chloro-2'-methoxy-benzamino-ethyl) N (7,8-dihydro-SH-thiapyrano-[4,3-d1-pyrimidin 2 yl) benzene-'sulfonamide; M.P.183l84 C. (recrystallized from methanol); as starting material there wasused 2-amino- 7,8-dihydro -'5H thiapyrano [4,3 d]-pyrimidine; M.P. 221C.

EXAMPLE 13 4- -chloro-2-methoXy-benzamino-methyl) -N- [4-methyl-S-isobutyl-pyrimidinyl- (2) ]-benzene-snlfonamide Using a methodanalogous to that described in EX- ample 12, 3.74 g.4-(5-chloro-2'-methoxy-benzaminomethyl)-benzene-sulfochloride (M.P. 113C.) were reacted in 6 ml. anhydrous pyridine with 1.65 g. Z-amino-4-methyl-S-isobutyl-pyrimidine. The purification of the compound wasalso carried out by the procedure in Example 12, except that in thepresent case the product was recrystallized a second time from methanol.There were thereby obtained 1.5 g. (30% of theory) 4-(5'-chloro-2-methoxy-benzamincrmethyl)-N-[4-methyl 5isobutylpyrimidinyl-(2)]-benzenesulfonamide having a melting point of147-148 C.

The bloodsugarreducing activities of some of the newbenzene-sulfonamido-pyrimidines were compared with that of the knowncompounds, i.e., 2-benZene-sulfonamido-S-methoxy ethoxy pyrimidine and N-sulfanilyl- N -(n-butyl)urea. The blood sugar reducing activity Wasmeasured in the rabbit following administration of the test compounds.In each instance the threshold dose was determined, that is the smallestdose of test compound sufiicient to effect a significant reduction inthe blood sugar values. As set forth in the table, the data is reportedas relative blood sugar reducing activities, i.e., referred to the bloodsugar reducing activity of N sulfanilyl-N (n-butyl)-urea equal to 1. Asdetermined by the above procedure the threshold dose of N -sulfanilyl-N-(nbutyl)-urea amounted to 200 mg./kg.

TABLE Relative blood sugar reducing activity (rab- No bit i.v.) Compound1 2,000 4-(fi-5-chlor-2-methoxy-benzami11o-ethyl)-N-[4-methyl-S-isobutyl-pryrlmidinyl-(2)]- benzene-sulfonamide.

2 80 4-({3 5-chlor-2-methoxy-benzamlno-ethyl)- iN-[4-l iityl-pyrimidinyl-(2)]-benzene-sulonarm e.

3 80 4-(B-5-chlor-2-methoxy-benzamino-ethyl)-N-[f4-isobuyl-pyrimidinyl-(2)]-benzenesul onami e.

4 800 4-(6-5chlor-2-methoxy-benzamino-ethyl)-N-[4-methyl-5-propyl-pyrlmidinyl-(2)]- benzene-sulionamide.

5 2, 000 4-(6-5-ehlor-2-methoxy-benzamino-ethyl)-N[4-methyl-5-isopropyl-pyrimidinyl-(2)]- benzene-sulfonamide.

6 800 4(fl-5-chlor-2-methoxy-benzamino-ethyl)-N-[5,6,7,8-tetrahydro-quinazolinyl-(2)]- benzene-sulionamide.

7 8, 000 4-(B-5'-chlor-2-ethoxy-benzamino-ethyl)- N -[4-n1ethyl-5-isopropyl-pyrimidinyl- (2)]- benzene-sultonamide.

8 8, 000 4-(5-5-chlor-2-ethoxy-benzamino-ethyl)-N-[4-methyl-5-isobutyl-pyrimidinyl-(2)]- benzene-sultonamide.

9. 80 4-(B-ethoxycarbonylaminoethyl)-N-[4-methyliidsobugyl-pyrimidinyl-(2)]-benzene-sulonami e.

10 400 4-(6-4-chlor-2-methoxy-benzamino-ethyl)-N-[4-methyl-5-isobutyl-pyrimidinyl(2)]- benzene sulfonamide.

11 4, 000 4-(8-5-brom-2-methoxy-benzamino-ethyl)-N-[4-methyl-5-isobutyl-pyrimidinyl-(2)]- benzene-sulfonamide.

12 800 4-(fl-3-methoxy-thenoyl-(2)-amino-ethyl)-N-[4-methyl-5-isobutyl-pyrimidinyl(2)]- benzene-sulfonamide.

Relative blood sugar reducing activity (rabbit i.v.)

Compound 4-(fi-3-chlor-benzamino-ethyl)-N-[5,6,7,8-

tetra-hydroquinazolinyl-(2)]-benzene-sulfonamide.4-(B-2-meth0Xy-5-methyl-benzamlno-ethyl)-N-[5,6,7,8-tetrahydroquinazolinyl-(2)]- benzene-sulfonamide.4-(B-phenylmercapto-acetamino-ethyl)-N- [5,6,7,8-tetrahydroquinazollnyl-(Z)l-benzenesultonamide.4-(B-cyclohexancarbonamino-ethyl)-N-[5,6,7,8-

tetrahydroquinazolinyl-(2)]-benzene'su1- tonamide. 4-(fl-2-rnethoxybenzamino-ethyl)'N-[5,6,7,8-

tetrahydroqumazolinyl-(2)]-benzenesulionamide.4-(B-3-methyl-3-phenyl-ureido-ethyl)-N-[4-methyl-5-isobutyl-pyrimidinyl-(2)]-benzenesulionamide.4-(Bindolln-1-carbonamino-ethyl)-N-[5,6,7,8-

tetra-hydroqulnazolinyl-(2)]-benzenesultonamide.4-(fl-benzaminoethyD-N-(6,7,8,9-tetrahydrofiH-cyclohepta[d]pyrimidin-2-yl)-benzenesultonamide.4- (fl-y-tluorbenzammo-ethyl)N-[4-methyl5-propyl-pyrimidinyl-(2)]-benzene-sulfon- (Comparison) The increase inactivity of the compounds of the invention as compared to2-benzenesulfonamido-S-methoxyethoXy-pyrimidine amount to at least8-fold and up to 800-fold.

The threshold dose for the compounds in accordance with the inventiondetermined in the rabbit and via the i.v. route amounted to 0025-25mg./kg. for oral administration, the effective threshold dose similarlyamounted to about 0.0252.5 mg./kg.

In normal clinical use, the compounds can be employed in both the freeand the salt form, and it is to be understood that the claims thereofcover the salts as well as the fundamental compounds. The activity ofthe compounds is independent of whether they are in salt form orotherwise. Salts may be prepared by any of the well known standardmethods. While the salt normally employed is the alkali salt andpreferably the sodium salt, the compounds have been prepared in the formof other salts, such as potassium, ammonium, etc.

The products of this process may be combined with a pharmaceuticalcarrier for administration to humans in an amount to attain the desiredblood sugar reducing eflect. Such carriers are either solid or liquid.Exemplary of solid pharmaceutical carriers are lactose, cornstarch,mannitol, talc, etc. The compounds of this invention are mixed with acarrier and filled into hard gelatin capsules or tabletted with suitabletabletting aids, such as magnesium stearate, starch, or otherlubricants, disintegrants or coloring agents. If combination with aliquid carrier is desirable, a soft gelatin capsule is filled with aslurry or other dispersion of the novel compounds in soya-bean, corn orpeanut oil. Aqueous suspensions or solutions are prepared for alternate,oral or parenteral administration.

The dosage of the novel compounds of the present invention for thetreatment of diabetes depends in the main on the age, weight andcondition of the patient being treated. The preferable form ofadministration is via the oral route in connection with which dosageunits containing 0.5-50 mg. of active compound in combination with asuitable pharmaceutical diluent is employed. One or two unit dosages aregood from one to four times a day.

We claim:

1. A compound selected from the group consisting of sulfonamides of theformula wherein X is an alkylene containing from 1 to 4 carbon atoms, Ais a member selected from the group consisting of lower alkyl, loweralkoXy, phenyl, substituted phenyl containing up to 2 substitutentsselected from the group consisting of halogen, lower alkyl and loweralkoxy; phenyloxy lower alkyl, phenyl mercapto lower alkyl cycloalkylhaving not more than 6 carbon atoms, thienyl, phenyl lower alkyl and agroup having the formula:

wherein V and W are each selected from the group consisting of loweralkyl and phenyl and when taken together with the nitrogen atom to whichthey are attached from an indoline ring; R is a member selected from thegroup consisting of hydrogen and lower alkyl, and R and R are joined toform a ring of 3 to methylene groups, wherein one methylene group can bereplaced by a sulfur atom and the pharmaceutically acceptable alkalisalts thereof.

2. A compound according to claim 1 designated 4-(5- 5chlor-2'-methoxy-benzamino-ethyl) N-[5,6,7 tetrahydroquinazolinyl-(2)]-benzene-sulfanamide.

3. A compound according to claim 1 designated 4-(fi-2'-methoxy-5'-methyl benzamino-ethyl) N [5,6,7,8-tetrahydroquinazolinyl-( 2) ]-'benzene-sulfonamide.

4. A compound according to claim 1 designated 4-(5-5-chlor-2'-methoxy-benzamino-ethyl)-N-(6,7,8,9 tetra- 12hydro-SH-cyclohepta[d]pyrimidin-2 yl) benzene-sulfonamide.

5. A compound according to claim 1 designated 4-(5- benzamino-ethyl) N[5,6,7,8 tetrahydroquinazolinyl- (2) ]-benzene-sulfonamide.

6. A compound according to claim 1 designated 4-(fiethoxycarbonyl ethyl)N [5,6,7,8 tetrahydroquinazolinyl- 2 -benzene-sulfonamide.

7. A compound according to claim 1 designated 4-( 8- acetaminoethyl) N[5,6,7,8 tetrahydroquinazolinyl- 2) ]-benzene-sulfonamide.

8. A compound according to claim 1 designated 4-(fi-3-chloro*benzamino-ethyl) N [5,6,7,8-tetrahydroquinazolinyl- (2)]-benZene-sulfonamide.

9. A compound according to claim 1 designated 4-(;8-phenylmercapto-acetamino-ethyl) N [5,6,7,8-tetrahydroquinazolinyl- 2)]benzene-sulfonamide.

10. A compound according to claim 1 designated 4-(5-cycloheXane-carbonamino-ethyl) N [5,6,7,8 tetrahydroquinazolinyl- 2)]-benzene-sulfonamide.

11. A compound according to claim 1 designated 4-(5- 2'-methoxybenZamino-ethyl) N [5,6,7,8-tetrahydroquinazolinyl- (2)]-benzene-sulfonamide.

12. A compound according to claim 1 designated 4-([?-indoline-l-carbonamino-ethyl) N [5,6,7,8-tetrahydroquinazolinyl- 2)]-benzene-sulfonamide.

13. A compound according to claim 1 designated 4-(l3-benzaminoethyl)-N-(6,7,8,9-tetrahydro 5H cyclohepta [d] -pyrimidin-2-yl)-b enzene-sulfonamide.

14. A compound according to claim 1 designated 4-(N-methyl-[$5-chloro-2'-methoxy-benzamino ethyl) N-(6,7,8,9-tetrahydro-5H-cyclohepta-[d]-pyrimidin-2 yl)-benzene-sulfonamide.

15. A compound according to claim 1 designated 4-(,8-5-chloro-2'-methoxy-benzamino ethyl) N (7,8-dihydro-5Hthiapyrano-[4,3-d] -pyrirnidin-2-yl)-benzene sulfonamide.

References Cited UNITED STATES PATENTS ALEX MAZEL, Primary Examiner R.J. GALLAGHER, Assistant Examiner U.S. Cl. X.R. 424-251 UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No,3%52 0r887 Dated 21,

Inventor(s) Ruth Heerdt et al It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

In the heading to the printed specification, lines 8 and 9 cancel "GmbHAntsgeicht, Mannheim, Germany" and insert Gesellschaft mit beschrankterHaftung, Mannheim-Waldhof,

Germany, a corporation of Germany. Column 3, line 25 ""amlnopyirimidine"should read aminopyrimidine line 42 "01E" should read or Column 8 line20 "phenoxyaceto' amino-" should read phenoxyacetaminoline 71 cancel "a"Column 9 line 36 after "folling" insert i.v. Column 11, line 30 insert acomma after "alkyl" second occurrence; line 47 "-N- [5 ,6 ,7-" shouldread Signed and sealed this 27th day of April 1971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E SCHUYLER, JR. Attestlng OfficerCommissioner of Patents FORM Poo5o uo'sg) USCOMM-DC 60375-P69 a uGOVIIIIIIIIT "manna OFFICE: Ill! o-su-su

